Monoclonal antibody technology is among the most notable scientific advances in the last quarter century. Rapid translation of this research has prolonged the survival of thousands of patients with cancer. Despite the promising activity of monoclonal antibodies, including rituximab, trastuzumab (herceptin), and cetuximab, the response rates among patients with either refractory or advanced cancer are suboptimal at less than 25%. One of the primary mechanisms of antitumor action is through antibody dependent cell-mediated cytotoxicity (ADCC) whereby a natural killer (NK) cell bearing an Fc receptor binds to the antibody-targeted tumor cell and mediates the killing function. Conventional cytotoxic chemotherapies induce myelosuppression, decreasing the population of NK cells, thereby reducing the efficacy of ADCC. In contrast, therapies which augment NK cell function uniquely offer the ability to improve activity of monoclonal antibodies without increasing toxicity to non-cancer cells. We have recently demonstrated that ADCC function can be augmented and target cell killing can be enhanced by a second antibody against CD137, an NK cell activation cell surface molecule. We hypothesize that by triggering the activation marker, CD137, on NK cells we can enhance the antitumor efficacy of monoclonal antibody therapy. To support this hypothesis we will demonstrate increased NK cell expression of CD137 occurs following NK cell exposure to antibody targeted tumors, including lymphoma by rituximab, breast cancer by trastuzumab, and colon and head and neck cancers by cetuximab. Second, we will investigate if stimulation of activated NK cells with agonistic anti-CD137 antibody enhances in-vitro cytotoxicity against antibody targeted tumors. Finally, we will determine if in-vivo treatment of xenografts of human lymphoma, breast cancer, and colon and head and neck cancers is synergistically enhanced by agonistic anti-CD137 antibody together with rituximab, trastuzumab, and cetuximab respectively. As agonistic anti-CD137 antibodies are currently in phase I/II clinical trials as monotherapy, if our hypothesis is valid, this strategy could be clinically translated immediately to any tumor for which there is already a proven monoclonal antibody therapy. )